Prolyl endopeptidase (PPCE) plays an important role in the degradation of biologically active peptides such as vasopressin which facilitates the process of learning and memory. Here, the effect of synthetic PPCE inhibitors (Z-Pro-, Suc-Pro-, Suc-Pyr-, Suc-Sar- and Z-prolinal) on the acquisition and retention of avoidance response was studied. Using mice of the ddY strain, tests were performed both in repeated trials of an active avoidance task and in a newly contrived one-trial passive-active avoidance task. The applicability of both tests for the evaluation of the anti-amnesic effect of the drugs was confirmed by the effect of scopolamine and arginine vasopressin (AVP). The most potent inhibitor, Z-Pro-prolinal, facilitated the acquisition of active avoidance response and retarded the extinction of the response. Other inhibitors also facilitated the retention of the acquired response. In the one-trial passive-active avoidance test, the facilitating effect of the PPCE inhibitors on the acquisition was parallel to their activity as a PPCE inhibitor. Scopolamine-induced amnesia was also improved by the inhibitors. These results suggest that the anti-amnesic effect of PPCE inhibitors is partially attributed to their inhibitory effect on the breakdown of AVP in the brain.

View full abstract

The effect of streptozotocin-induced diabetes on ¹²⁵I-labeled epidermal growth factor (EGF) binding was studied in microsomal membranes from rat liver. The binding of EGF in membranes from diabetic animals was significantly low, the value being about 60% of the control level. Scatchard analysis of the binding data clearly showed that the decrease in EGF binding was due to a decrease in the number of receptors. Treatment of diabetic animals with insulin restored EGF receptors to control levels, whereas the treatment with triiodothyronine had no effect. Serum EGF concentrations measured were almost the same among the control, diabetic, and insulin-treated diabetic groups. These results suggest that insulin deficiency in vivo causes a decrease in hepatic EGF receptors.

View full abstract

Rat mast cells were purified by a Percoll gradient, and the granules were isolated from the sonicated mast cells on a Percoll gradient. The granules were shown to contain a diphosphoinositide kinase which catalyzes the formation of triphosphoinositide (TPI) from diphosphoinositide (DPI). The enzyme requires ATP and Mg²⁺ for the activity. TPI formation is almost completely dependent on MgCl₂ or MnCl₂, and maximal response is observed at 20 mM or 1 mM, respectively. The Km for ATP is 3μM. TPI formation in the granules is dependent on the reaction time. The maximal response is seen at 23°C. NaCl, KCl, Na₂HPO₄ and KH₂PO₄ have no effect on the activity. One hundred μM adenosine, AMP, ADP, and 10μM cyclic AMP inhibit the kinase activity.

View full abstract

Anti-inflammatory, analgesic and anti-pyretic activities of orally administered TA were investigated in experimental animals. Against acetic acid-induced vascular permeability in mice, carrageenin-induced hind paw edema in rats and ultra-violet ray-induced erythema in guinea pigs, TA produced a dose related inhibition at doses of 40 ?? 160 mg/kg, 10 ?? 40 mg/kg and 10 ?? 40 mg/kg, respectively. TA produced no inhibition against histamine-induced vascular permeability even at a dose of 200 mg/kg in rats. Cotton pellet-induced granuloma and adjuvant-induced arthritis in rats were significantly inhibited by repeated administration of TA at a dose of 50 mg/kg/day for 6 days and 25 mg/kg/day for 6 days, respectively. TA showed a dose related analgesic effect at a dose of 50 ?? 200 mg/kg in acetic acid writhing, Randall-Selitto and adjuvant arthritic pain methods. A high dose of TA was needed to produce an analgesic effect in the pressure method using mice. TA produced an anti-pyretic effect against the pyrexia induced by yeast in rats. On the other hand, TA showed no effect against normal body temperature in rats. These results suggest that anti-inflammatory, analgesic and anti-pyretic activities of TA are generally a little weaker than those of ibuprofen, and the mode of action of TA is similar to that of a typical acidic non-steroidal anti-inflammatory drug such as ibuprofen, indomethacin or phenylbutazone. The ulcerogenic activity of TA was about 2 and 4 times weaker than that of ibuprofen in rats and mice, respectively. TA showed a protective effect against gastric necrosis induced by HCl. In conclusion, TA is a potent anti-inflammatory compound, and the slight ulcerating effect of TA on the stomach may be attributed to its protective effect on the gastric mucous membrane.

View full abstract

Effect of MN-1695, a new cytoprotective antiulcer agent, on 0.2N HCl-induced gastric surface epithelial cell damage was investigated by optical and transmission electron microscopy in rats. Tissue examination after five minutes exposure to 0.2 N HCl showed extensive damage of the surface epithelial cells: dilatation of intercellular spaces including marked edema of lamina propria. It was found that MN-1695 (3 mg/kg) pretreatment prevented such 0.2 N HCl-induced damage of the surface epithelial cells, and it reduced the percentage of damaged mucosa, but not significantly.

View full abstract

Interaction of Platonin (Pl) and dexamethasone (DM) or testosterone propionate (TP) on bone wound healing was studied by measuring the areas of wound holes which were made in the rat parietal bone. The result was compared with that of the growth of the femur. 1) No significant difference was observed between the control group and Pl groups (1, 10 and 100 μg/kg, s.c., for 4 weeks) on the wound hole area or the length, weight, calcium content (Ca) or hydroxyproline content (HP) in the femur. 2) The bone wound healing was delayed by DM (2 mg/kg, s.c., for the first 2 weeks). The inhibition of growth was also observed in the femur length and weight, but no significant effect of DM was observed in the Ca and HP of the femur. The combination of Pl and DM promoted the recovery from delayed bone wound healing and femur weight gain caused by DM. 3) No significant effects of TP (4 mg/kg, s.c., for the first 2 weeks) were observed on the wound healing and the femur growth, but an increase of the femur weight and Ca was observed by the combination of Pl and TP. These results indicate that Pl promotes the recovery from delayed bone wound healing and femur weight gain by DM, although no significant effects were observed in bone growth and bone wound healing by the administration of Pl alone. It is also suggested that a combination of Pl and TP promotes bone growth and mineralization.

View full abstract

The effect of terodiline on the function of urinary bladder was investigated in anesthetized rats. When saline was infused continuously into the urinary bladder of rats, terodiline (1 ?? 10 mg/kg, i.v.) prolonged the time to micturition in a dose-dependent manner. When enough saline was infused into the urinary bladder to induce the voiding contraction in urethra-ligated rats, terodiline (1 ?? 10 mg/kg, i.v.) and verapamil (1 mg/kg, i.v.) abolished the contraction, of which amplitude and frequency were partially inhibited by atropine (1 mg/kg, i.v.). Efferent discharge from the pelvic nerve on the micturition reflex was inhibited by terodiline (3 mg/kg, i.v.). Both of the bladder contractions evoked by the electrical stimulation of the peripheral or central cut end of the pelvic nerve were dosedependently inhibited by terodiline (1 ?? 10 mg/kg, i.v.). At 3 mg/kg or more, terodiline significantly inhibited the contraction, and the effects were long lasting. The effect of atropine (1 mg/kg, i.v.) was similar to that of terodiline (3 mg/kg, i.v.). Increase in frequency of urination and decrease in total urinary volume per micturition after the bilateral transection of the hypogastric nerve were improved after on oral administration of terodiline (1 ?? 10 mg/kg).

View full abstract

We studied the effects of OGT, SST, AS and DST on ethanol- and aspirin-induced reduction of gastric transmucosal potential difference (PD) in rats as an index of gastric mucosal damage, and these effects were compared with those of sucralfate, 16, 16-dimethyl-prostaglandin E₂ (DMPGE₂), cimetidine and proglumide. 1) OGT and SST as well as sucralfate and DMPGE₂ significantly inhibited the PD reduction induced by ethanol and aspirin. 2) AS and DST as well as cimetidine significantly inhibited the PD reduction induced by aspirin, but not by ethanol. 3) proglumide did not influence the PD reduction induced by ethanol and aspirin. 4) OGT alone, like sucralfate and proglumide, showed no influence on the basal PD, while SST, AS and DST, like DMPGE₂ and cimetidine, increased the basal PD. These results suggest that OGT, SST, AS and DST protect the gastric mucosal barrier, and this effect of OGT differs from that of SST, AS and DST.

View full abstract

The mode of action of Nocardia rubra cell wall skeleton (N-CWS) on Meth A fibrosarcoma (Meth A) was studied in BALB/c mice. N-CWS suppressed or regressed the intradermal growth of syngeneic Meth A cells in normal BALB/c and athymic BALB/c mice. The intradermally and subcutaneously infiltrated cells harvested from injection sites of N-CWS in normal mice showed in vitro cytotoxic activity against Meth A cells. Pretreatment of normal BALB/c mice with immunosuppressing agents such as hydrocortisone, carrageenan, or silica particles significantly reduced the anti-tumor effect of N-CWS. The growth of Meth A cells, rechallenged into BALB/c mice in which Meth A cells had once been suppressed or regressed by N-CWS treatment, was also inhibited, but not in similarly treated athymic nude mice. This resistant mechanism was shown to be dependent on cellular components but not on humoral components by the Winn assay. The present results suggest that N-CWS exerts its anti-tumor activity by mediation of the immune system of the host and that the main effector cells in the early stage of tumor rejection are macrophages; T cells may also be involved in the later stage.

View full abstract